Background

Glanders and melioidosis are related diseases produced by bacteria of the Burkholderia species, which are gram-negative rods. The two diseases have similar symptoms and similar pathophysiologic consequences.

Glanders and melioidosis are of interest because of significant study for potential weaponization by the United States and other countries in the past. During World War I, glanders was believed to have been spread to infect large numbers of Russian horses and mules on the Eastern Front. The Japanese infected horses, civilians, and prisoners of war during World War II. The United States studied this agent as a possible biological warfare (BW) weapon in 1943-1944 but did not weaponize it. The former Soviet Union is believed to have been interested in glanders as a potential BW weapon, as well.

Burkholderia mallei (nonmotile, nonsporulating, obligate aerobic, gram-negative bacillus) is the causative agent of glanders, which is primarily a disease of animals such as horses, mules, and donkeys.
[1] Glanders has been only a rare and sporadic disease in humans, and no epidemics have been reported. In China during World War II, 30% of the tested horses were infected with glanders, but human cases were rare. The reason for the low transmission rate is not known. In the human population, Burkholderia mallei typically is found in persons with close and frequent contact with infected animals, such as veterinarians, animal caretakers, abattoir workers, and laboratory personnel.

Melioidosis, also known as Whitmore disease, is caused by the bacterium Burkholderia pseudomallei (a motile, aerobic, non–spore-forming bacillus).
[2] It is clinically similar to glanders, although the epidemiology differs. The bacteria thrive in tropical climates. The disease is endemic in Southeast Asia and Australia, and is also found in the Middle East, India, and China (essentially tropical areas between latitudes 20 degrees north and south). Sporadic melioidosis cases have been reported in the United States (typically 0-5 cases per year, usually among immigrants and travelers). However, the worldwide incidence appears to be rising as a result of increased travel and epidemiological sophistication. Both humans and other susceptible animals may contract the disease.

Both organisms are considered potential biological warfare agents, especially in the aerosolized form.
[3] In fact, because they are highly infectious especially by inhalation and because of their resistance to routine antibiotics, both bacteria have been classified as category B priority pathogens by the National Institutes of Health and the Centers for Disease Control and Prevention (CDC).
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Pathophysiology

Glanders is caused by Burkholderia mallei (formerly Pseudomonas mallei). The bacteria exist only in infected susceptible hosts and are not found in water, soil, or plants. In nature, humans typically acquire glanders from equids via direct contact with broken skin or mucous membranes. While transmission through intact skin has been reported, it is not well documented. A secondary mode of transmission can be through inhalation of droplets from an infected equid or patient.

Once in the host, synthesis and release of certain toxins occur. Usually, the amount is insignificant, and no clinical disease process ensues. However, if a large quantity of the organism is incorporated, the amount of toxin is sufficient to cause specific symptoms. Antibiotics are of little use. The toxins include pyocyanin (blue-green pigment that interferes with the terminal electron transfer system), lecithinase (causes cell lysis by degrading lecithin in certain cell membranes), collagenase, lipase, and hemolysin.

Melioidosis is an infectious disease caused by B pseudomallei (formerly P pseudomallei). The organism is distributed widely in the soil and water of the tropics. It is spread to humans through direct contact with a contaminated source, especially during the rainy season. The disease usually occurs in the fourth and fifth decades of life, especially among those who have chronic comorbidities such as diabetes, alcoholism, immunosuppression, and renal failure.

B pseudomallei is considered a good candidate as a bioweapon because it is easily available in the tropics, it is fairly easy to cultivate, it is sturdy, and it has a high potential to become bacteremic, thereby increasing morbidity and mortality. The incubation period in naturally acquired infections can vary from days to months to years. The incubation period after an aerosol attack is expected to be from 10-14 days.

Glanders and melioidosis produce similar clinical syndromes.

Localized form

Bacteria enter the skin through a laceration or abrasion, and a local infection with ulceration develops. The incubation period is 1-5 days. Swollen lymph glands may develop. Bacteria that enter the host through mucous membranes can cause increased mucus production in the affected areas.

Pulmonary form

When bacteria are aerosolized and enter the respiratory tract via inhalation or hematogenous spread, pulmonary infections may develop. Pneumonia, pulmonary abscesses, and pleural effusions can occur. The incubation period is 10-14 days. With inhalational melioidosis, cutaneous abscesses may develop and take months to appear.

Septicemia

When bacteria is disseminated in the bloodstream in glanders, it is usually fatal within 7-10 days. The septicemia that develops affects multiple systems, and cutaneous, hepatic, and splenic involvement may occur. With melioidosis, bacteremia is observed with chronically ill patients (eg, patients with HIV, patients with diabetes). They develop respiratory distress, headaches, fever, diarrhea, pus-filled lesions on the skin, and abscesses throughout the body. Septicemia may be overwhelming, with a 90% fatality rate and death occurring within 24-48 hours.

Chronic form

The chronic form involves multiple abscesses, which may affect the liver, spleen, skin, or muscles. This form also is known as farcy in glanders disease. Melioidosis, in addition to this chronic form, can become reactive many years after the primary infection.

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Epidemiology

Frequency

United States

Glanders was eliminated from US domesticated animals in the 1940s. One human case of glanders in a laboratory worker occurred in 2000. This is the first human case reported in the United States since 1945.
[5]

A few isolated cases of melioidosis have occurred in the United States. Confirmed cases range from 0-5 each year and occur among travelers, immigrants, and intravenous drug users.
[6]

From 2008 to 2013, 37 confirmed cases of melioidosis in the United States and Puerto Rico were reported to the CDC's Bacterial Special Pathogens Branch of human infections, including 34 human cases and three animal cases. Among individuals with a documented travel history, 64% of reported cases occurred in those with a travel history to endemic areas. During the study period, two incidents of occupational exposures were reported, and no human infections occurred.
[7]

International

Glanders is endemic in Africa, Asia, the Middle East, Central America, and South America.

Melioidosis is endemic in Southeast Asia and northern Australia. In 2011, melioidosis was diagnosed in six individuals in a desert region of Australia over a 4-month period following unusual heavy rains and flooding.
[8] Nevertheless, even in these zones, the diagnosis may be delayed.
[9] Melioidosis has also been observed in the South Pacific, Africa, India, the Middle East, Central America, and South America. A case of young boy with laboratory-confirmed melioidosis was reported from Malawi in 2011, and the authors' review of the literature indicates that the number of cases seems to be increasing in Africa.
[10]

In India, melioidosis has acquired the status of a newly emerging infectious disease.
[11] One study in India involving a series of patients with melioidosis revealed that skin and soft-tissue involvement (16%), liver abscess (16%), and bone and joint involvement (16%) were the most common presentations of this disease in patients with diabetes. Septicemia and major organ failure resulting in death was not uncommon.
[12]

Mortality/Morbidity

The mortality rate in the pulmonary form of glanders is 90-95% if untreated and 40% if treated. The mortality rate in the septicemic form of glanders is greater than 95% if untreated and 50% if treated. The mortality rate in the cutaneous form of glanders is 90-95% if it becomes systemic and if untreated but 50% if properly treated. For the chronic form of glanders, the mortality rate may be 50% despite treatment.

Melioidosis has had a reported mortality rate up to 90% if disseminated septicemia is present. In Australia, the mortality rate is 19%, whereas in Thailand it is 50%. It is most widespread in Thailand, where in one hospital, it was responsible for 19% of community-acquired sepsis and 40% of deaths from community-acquired septicemia.
[13] The fatality rate of melioidosis is greater in people with specific comorbidities, such as diabetes mellitus, renal dysfunction, or chronic pulmonary disease, and in people who are immunosuppressed for one reason or another.

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Dahna Batts, MD, Alan H Hall, MD, and Thomas W McGovern, MD, to the development and writing of this article.